tbuckley/cabot-search huggingface dataset:
Abstract P1165: Gut Microbial Peptide Induced Cardiac Inflammation Via Cyclin Dependent/NFkB Signaling In Macrophages
Authors: Prabhat Ranjan, Roshan Dutta, Karen Colin, Craig Maynard, Suresh K Verma
Journal: Circulation Research (2023)

Background: Millions of people in the United States are affected by Inflammatory Bowel Disease (IBD). Recently, gut dysbiosis and impaired gut-barrier permeability are known to contribute to cardiovascular diseases in IBD patients. However, its mechanisms are poorly understood. Here, we hypothesized that gut derived bacterial metabolites (such a peptidoglycan in this case) in a mice colitis model, promotes cardiac inflammation and heart failure. Methods: To induced colitis WT mice were treated with control/DSS (dextran sodium sulfate). Heart and intestine were collected to evaluate inflammatory genes expression(qPCR), immune cell infiltration (FACS), and intestinal permeability (WB and immunohistochemistry). Blood was collected to quantify peptidoglycan (PGN) level. The effect of PGN on NFκB inflammatory pathways was evaluated in macrophages. Results: Echo-data showed cardiac dysfunction in DSS mice. Deteriorated intestinal villi in Masson’s trichrome staining and decreased Occludin and increased PV-1 in western data revealed leaky gut in DSS treated mice. Remarkably, PGN level was significantly increased in blood plasma 3 weeks following DSS treatment. Real-time gene expression data of pro-inflammatory cytokines (IL-6, IL-1 and TNFα) and fibrosis associated genes (col1α1, fibronectin) were increased in DSS mice heart. Increased CD68 expression in the immunostaining data of DSS mice heart indicated the recruitment of inflammatory macrophages. Intriguingly, we observed that CDK9 expression significantly increased upon PGN treatment leading to an increase in NFκB. Next, we inhibited CDK9 before PGN treatment and surprisingly we found that CDK9 inhibition reduces the effect of PGN. Conclusion: Taken together, data suggest that in gut dysbiosis state, PGN leaks into the blood and causes CDK9 mediated NFκB upregulation and cardiac inflammation.
Abstract P3012: Routine Monitoring For Intracardiac Thrombosis And Pulmonary Embolism With Intraoperative Transesophageal Echocardiography In Orthotopic Liver Transplantation
Authors: Niki Noe, Akanksha Girish, Lorenzo De Marchi
Journal: Circulation Research (2023)

Background: Intracardiac thrombosis (ICT) and pulmonary embolism (PE) are significant intraoperative complications during orthotopic liver transplantation (OLT). Despite the high mortality associated with these events, current monitoring practices are inadequate at detecting these complications during OLT. Transesophageal echocardiography (TEE) allows continuous monitoring of myocardial function and detection of ICT/PE. In this study, we aim to report the incidence of ICT/PE during OLT at our center and to advocate for the use of intraoperative TEE as a standard monitoring tool. We also propose a medical management algorithm stratified by the severity of RV dysfunction and pulmonary artery pressure (PAP) in cases of ICT with/without PE. Methods: We conducted a single-center retrospective chart review of OLT patients with intraoperative TEE monitoring from March 13, 2019 - March 13, 2023. Intraoperative data of interest included hemodynamics, RV dysfunction, PAP, presence of ICT and/or PE as identified on TEE and associated medical management. RV dysfunction was graded as mild, moderate, or severe reduction in cardiac contractility. Secondary outcome was mortality during index hospitalization. Results: We identified 99 patients at our center who had intraoperative TEE monitoring during OLT. Prevalence of ICT in this population was 9.09% (n=9), of which 44.4% (n=4) developed hemodynamically significant PE. ICT patients who remained hemodynamically stable were observed without intervention (33%, n=3). Heparin was administered to prevent thrombus enlargement in patients with an increase in PAP but no significant RV dysfunction detected on TEE (22%, n=2). Those showing signs of hemodynamically significant PE with moderate or severe RV failure were given tissue plasminogen activator (tPA) for thrombolysis (44%, n=4). Perioperative mortality among all ICT patients was 44.4% (n=4) due to hemorrhagic shock secondary to coagulopathy and heart failure. Conclusion: The results of this study show the utility of routine TEE use in intraoperative monitoring for identifying ICT and PE in OLT patients, given the high mortality associated with these complications. TEE also allows for a stepwise approach to medical management based on RV function and PAP.
Abstract P1166: O-GlcNAcylation Regulates Protein Synthesis In Cardiomyocytes Through Effects On The Translational Regulator Eif2α
Authors: Kyriakos Papanicolaou, Jessica Jung, Wenxi Zhang, Deepthi Ashok, D.Brian Foster, Brian O’Rourke, Natasha Zachara
Journal: Circulation Research (2023)

The regulated and reversible modification of Ser/Thr residues by O-linked N-Acetylglucosamine (O-GlcNAc) is termed O-GlcNAcylation. O-GlcNAc cycling on and off proteins is regulated by two conserved enzymes, the ‘writer’ O-GlcNAc Transferase (OGT) and the ‘eraser’ O-GlcNAcase (OGA). Crucially, O-GlcNAcylation is implicated in nutrient sensing, cell growth and stress adaptation. Despite these significant roles, the precise pathways impacted by O-GlcNAcylation and what key substrate proteins are involved remain incompletely understood. A hallmark of cardiomyocyte hypertrophy is the rapid production of new proteins that assemble into the contractile machinery of the growing myocyte. eIF2α is a rate-limiting factor in translation initiation. Interestingly, phosphorylation of eIF2α causes the arrest of general mRNA translation and favors the translation of stress-adaptive mRNAs. In the present work we investigated whether altering O-GlcNAcylation affects nascent protein synthesis (NPS) in hypertrophic cardiomyocytes. NPS was significantly elevated by the agonist phenylephrine, and this response was suppressed by OSMI-1 (OGT inhibitor). Moreover, we found that OGT-inhibited cells had increased phosphorylation of eIF2α. Additionally, we found increased protein levels of the stress adaptive factors Atf4 and Chop, whose mRNA translation is favored when eIF2α is phosphorylated. ISRIB, a small molecule designed to suppress the effects of phospho-eIF2α in altering translation, significantly prevented OSMI-1-induced accumulation of Atf4. Furthermore, we used metabolic labeling of glycans in cells, coupled with alkyne-azide ‘click’ chemistry and streptavidin pull-down, to show that eIF2α can be O-GlcNAcylated in cardiomyocytes. Furthermore, protein enrichment followed by mass spectrometry identified potential sites of O-GlcNAcylation on eIF2α. Taken together, these results highlight a novel role of O-GlcNAcylation on cardiomyocyte protein synthesis through the regulation of eIF2α. Future investigations will characterize the upstream mechanisms that promote eIF2α phosphorylation in OGT-inhibited cells and investigate the implications of direct eIF2α O-GlcNAcylation on hypertrophic protein synthesis in cardiomyocytes.
Abstract P1042: Stem Cell Models Reveal Sarcomere Inhibition As A Potential Treatment For Pediatric Restrictive Cardiomyopathy
Authors: David Staudt, Ricardo Serrano, Mark Mercola
Journal: Circulation Research (2023)

Introduction: Pediatric Restrictive Cardiomyopathy (RCM) is a genetic cardiomyopathy resulting from profoundly increased stiffness of the wall of the cardiac ventricle with normal or low normal contractility. Treatment options are limited, with most patients necessitating heart transplant. Therapies that can improve diastolic function are needed for this severe disease. Recently, direct inhibition of the sarcomere with mavacamten, a cardiac myosin antagonist, has been shown to be effective in treating a related disease, Hypertrophic Cardiomyopathy (HCM), in adults. However, whether it would be useful for the diastolic dysfunction seen in RCM is unknown. Hypothesis: Treatment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived from RCM patients with mavacamten will rescue diastolic deficits. Methods: Cardiomyocytes were differentiated from induced pluripotent stem cells (iPSCs) originally derived from a pediatric patient with RCM, as well as a paired isogenic CRISPR-corrected line. Cells were treated with increasing doses of mavacamten and contractility and resting tension were measured using a novel traction force microscopy platform. Results: At baseline, RCM cells showed elevated contractility, resting tension, and calcium sensitivity compared to their isogenic control. Mavacamten treatment decreased both contractility and resting tension of RCM cardiomyocytes. Conclusions: Mavacamten improves both systolic and diastolic derangements in an hiPSC model of RCM.
Abstract P2044: Silencing The LncRNA <i>Vesper</i> During Right Ventricle Pressure Overload Worsens Hypertrophic Remodeling And Function
Authors: Jordy M Kocken, Pedro Mendes-Ferreira, Henry del Marmol, Tim Davalan, Raquel Figuinha Videira, Adelino F Leite-Moreira, Paula A da Costa Martins
Journal: Circulation Research (2023)

Pulmonary arterial hypertension (PAH) is a rare disease that includes familiar and idiopathic forms. Increased pressure in the pulmonary artery leads to pressure overload of the right ventricle (RV) and subsequent hypertrophic remodeling to maintain cardiac output (CO). While many therapies are available for the hypertrophic left ventricle (LV), the RV is known to involve distinct remodeling pathways and unfortunately, these are poorly understood, and no cure is available. To identify new regulatory mechanisms, total RNA sequencing was performed on hypertrophied mouse RV tissue. Focusing at differentially expressed long non-coding RNAs (lncRNAs), one specifically, Gm38399 , was observed to be consistently upregulated in the diseased RV compared to healthy controls. Compared to LV tissue, there was a similar expression at baseline, but interestingly, no increase in expression during LV hypertrophy. Therefore, we named this lncRNA right VE ntricular S pecific P ressure ov ER load ( Vesper ). To elucidate the mechanism, we determined the subcellular localization of Vesper , by subcellular fractioning followed by qPCR. Using Xist as nuclear, and Gapdh as cytoplasmic control, we found Vesper to be entirely nuclear. Furthermore, we were able to silence Vesper in vitro by using a specific GapmeR. Not only Vesper was silenced, but we also found two neighboring genes to be affected, namely Nav1 and Phlda3 . Interestingly, these genes were also differentially expressed in the diseased RVs. To determine the mechanism in vitro , chromatin isolation by RNA purification (ChIRP) was performed and the crosslinked RNA, DNA, proteins stored for further analysis. We also treated mice that underwent pulmonary artery banding (PAB) or sham surgery, with a weekly intraperitoneal injection of 10 mg/kg bodyweight GapmeR or a vehicle control. After 4 weeks, the mice underwent hemodynamic analysis before the RV tissue was isolated for histology and molecular analysis. Surprisingly, silencing of Vesper exacerbated pathologic RV remodeling, also in mice that received sham surgery. While further investigation is needed to understand the role of Vesper in PAH, our results so far suggest that expression of Vesper is necessary to maintain RV function during pressure overload.
Abstract P1164: Elevated Erk1/2 Signaling Contributes To The Development Of Diabetic Cardiomyopathy
Authors: Ruijie Liu
Journal: Circulation Research (2023)

Background: About 19%-26% of the obese patients develop diabetic cardiomyopathy (DCM) characterized by ventricular hypertrophy, fibrosis, and contractile dysfunction. Although many studies have investigated the potential causes of DCM, the pathophysiology of this disease has yet been to be fully characterized. Objective: To determine whether extracellular signal-regulated kinase 1/2 (ERK1/2) are involved in the development of DCM. Materials and Methods: Both streptozotocin (STZ)-induced type I and db/db type II diabetic mice were utilized to compare the ERK1/2 phosphorylation level in mouse hearts. To determine the gain-of-function of ERK1/2 signaling in DCM, both control and dual specific phosphatase 6 and 8 knockout mice (DKO) mice were administered streptozotocin (STZ) to induce elevated serum glucose. After 12 weeks of treatment, mouse body weight, heart weight/histology, and disease markers were compared. As a loss-of-function study, U0126 was utilized to inhibit ERK1/2 activity in both streptozotocin (STZ)-induced type I and db/db type II diabetic mice to determine whether DCM markers are influenced. Results: In both type I and II diabetic mouse hearts, ERK1/2 phosphorylation level was significantly elevated. STZ treatment for 2 weeks induced similar increases in serum glucose in both WT and DKO mice. After 12 weeks of STZ treatment, DKO mice developed greater cardiac atrophy and increased levels of ANF, BNP, beta myosin heavy chain gene expression. In comparison, U0126-mediated pharmacological inhibition of ERK1/2 for 12 weeks significantly improved the cardiac function in both type I and II diabetic mouse models. Conclusion: Elevated ERK1/2 signaling contributes to the process of DCM, suggesting ERK1/2 could be therapeutic targets for the treatment of this disease.
Abstract P3100: Mice Lacking S-nitrosoglutathione Reductase (gsnor <sup>-/-</sup> ), A Mouse Model Of Preeclampsia, Exhibit Increases In Oxidative And Nitrosative Stress And Deterioration Of Cardiovascular Structure And Function In The Mother Postpartum.
Authors: Raul A Dulce, Wayne Balkan, Joshua M Hare, Shathiyah Kulandavelu
Journal: Circulation Research (2023)

Introduction: Preeclampsia (PE), a leading cause of maternal mortality, is linked to persistent pathological changes in the heart, predisposing the mother to increased risk of chronic cardiovascular (CV) disease later in life. PE is characterized by increased S-nitrosylated (SNO) proteins and nitrosative stress. We recently showed that mice lacking S-nitrosoglutathione reductase (GSNOR -/ - mice), a denitrosylase that regulates protein S-nitrosylation, exhibit the clinical features of PE including maternal hypertension, blunted increase in cardiac output, abnormal remodeling of left ventricular (LV) cardiac structure, dysregulation in nitrosylation and increased nitrosative stress. We hypothesize that the aberrant nitrosylation and nitrosative stress seen during pregnancy persist postpartum (PP), leading to increased maternal susceptibility to CV injury. Methods: Pregnant control (WT [C57Bl/6J]) and GSNOR -/- mice (N=5) were examined at baseline, late-stage pregnancy (17.5 dpc) and 6 weeks PP. LV structure, cardiac output and stroke volume were determined using echocardiography (Vevo 2100). Cardiomyocytes (CM) were isolated at 6 weeks PP and ROS and peroxynitrite levels determined using fluorescent dyes. Results: In WT mice, all normal maternal CV adaptions to pregnancy, reverted to pre-pregnant levels 6 weeks PP. In contrast, GSNOR -/- mice exhibited increased cardiac output (+21% vs. -19% in WT), stroke volume (+21% vs. -41% in WT), and LV chamber dimension (+13% vs. -4% in WT) at 6 weeks PP, indicating high cardiac output LV cardiomyopathy. CM isolated from GSNOR -/- hearts showed ~5-fold more ROS generation (9.9x10 -4 ±9x10 -5 vs. 2.1x10 -4 ±1.5 x10 -4 ΔF/F max .min -1 ) and elevated peroxynitrite levels (0.318±0.011 vs. 0.243±0.012 ΔF/F 0 ) compared to WT at 6 weeks PP, suggesting the presence of oxidative and nitrosative stress. All changes P&lt;0.05. Conclusion: Postpartum GSNOR -/- (preeclamptic) mothers exhibited cardiac dysfunction characterized by high cardiac output LV cardiomyopathy, which was accompanied by elevated levels of oxidative and nitrosative stress. These changes may predispose the mother to higher risk for future CV injury.
Abstract P1046: Twenty-year Single-center Experience Of Catheter Ablation Of Ventricular Tachycardia And Progression To Heart Transplantation
Authors: Danielle M Mullis, Oluwatomisin O Obafemi, Sean Kumar, Augustine Kang, Joy Aparicio Valenzuela, Ornella Pelissero, Francois Haddad, Anson M Lee
Journal: Circulation Research (2023)

Objective: Orthotopic heart transplantation (OHT) is often used as salvage therapy after failed catheter ablation for ventricular tachycardia (VT). Little is published on the results of OHT after VT ablation, and predicting which ablation patients need transplantation is difficult. The purpose of this study is to examine the effect of OHT as a therapy for failed VT ablation and to identify echocardiographic measurements that might predict the need for transplantation. Methods: All adult patients who received VT ablations at our institution between 2001 and 2021 were identified. Follow-up data was collected until mid-2022. Echocardiograms obtained at the time of ablation were analyzed by hand tracing and Phillips QLab Advanced Quantification Software (Amsterdam, Netherlands). Survival distributions were compared using a Log Rank test. Continuous variables were analyzed using independent samples T-tests. Results: 205 adult patients underwent an elective VT ablation between 2001 and 2021. Of these patients, 40 were referred for heart transplant evaluation. Of these 40 patients, 18 underwent OHT. There was a significant survival benefit after VT ablation for those who underwent OHT versus those who were referred but did not undergo OHT. There was a mean of 2.42 years of increased survival after VT ablation for the patients who were referred and transplanted versus those referred and not transplanted (p=0.016). The mean survival of patients not referred for transplantation was 4.6 ± 3.4 years. The most common barrier to transplant was obesity (n=6). Factors significantly predictive for referral to transplantation after VT ablation were lower ejection fraction (EF) (33.8% versus 45.6%), increased global longitudinal strain, and decreased fractional shortening (p&lt;0.01, p&lt;0.001, and p=0.001, respectively). Conclusion: Patients ultimately referred for OHT after VT ablation had significantly more cardiac dysfunction at the time of ablation. Once referred, morbid obesity was the most common barrier to transplantation. Lower EF, along with increased strain, was predictive of the need for transplantation. Earlier counseling of weight loss for morbidly obese patients with VT and ventricular dysfunction might lead to better survival.
Abstract P2166: Cardioprotective Effect Of Angiotensin Converting Enzyme 2 Activation In Hesc-derived Cardiomyocytes Under Diabetic Condition
Authors: Sung Woo Cho, Ji Hee Sung, Jin Han, Hyoung Kyu Kim
Journal: Circulation Research (2023)

Diabetes mellitus (DM) is on the rise and has quickly become one of the most common and expensive chronic diseases in the world. DM and cardiovascular disease (CVD), the leading cause of morbidity and mortality in diabetic patients, have a close relationship. Diabetic cardiomyopathy (DCM) is a phenomenon comprising the deterioration in cardiac function and structure independent of coronary artery disease and other causes. However, there is still no specific and effective treatment of DCM. We investigated the cardioprotective effect of pharmacological activation of angiotensin converting enzyme 2 (ACE2) activator, diminazene aceturate (DIZE) in DCM in vitro model by using human embryonic stem cell (hESC)-derived cardiomyocytes under diabetic condition. In hESC-derived cardiomyocytes under diabetic condition, DIZE decerased the cardiomyocyte size and stabilized beating phenotypes. Furthermore, DIZE reduced the HF, cardiac hypertrophy, fibrosis, oxidative stress related gene expression, and ROS level and increased the mitochondrial function related gene expression and mitochondrial membrane potential. In transcriptome analysis, SERPINE1/PAI-1 and CCN2/CTGF are highly upregulated after DIZE treatment and might be candidate target genes of ACE2 activation. Collectively, ACE2 activation have a direct cardioprotective effect in hESC-derived cardiomyocytes under diabetic condition and can be a potential therapeutic target of DCM.
Abstract P1048: Lattice-Boltzmann Method Achieves Feasible Hemodynamic Analysis In Carotid Atherosclerosis With Low Computational Cost
Authors: Seung Hyun Park, Hyunwoo Cho, Hae Nam Ahn, Yeongchae Park, Kwang Won Kim, Brian Cho, Hojin Ha, Han Seo Ko, Doosang Kim
Journal: Circulation Research (2023)

Introduction: Atherosclerosis is a common cardiovascular pathophysiology that can lead to plaque-related complications, including stroke and myocardial infarction. Non-invasive hemodynamic analysis can provide valuable insights into the plaque's rupture vulnerability and growth progression. Computational fluid dynamics is widely studied to understand hemodynamic pathophysiology further; however, traditional computational fluid dynamics methods often require daily-based analysis time to visualize hemodynamic parameters. This study investigated the feasibility of using the lattice Boltzmann method (LBM) for hemodynamic analysis of atherosclerosis lesions. Methods: From ten carotid artery stenosis patients, 20 carotid artery models were generated and analyzed using LBM. Hemodynamic parameters, including time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT), were compared between the stenotic lesion and contralateral control sides. The patient-specific boundary conditions were applied. Their cardiac cycle was subdivided into three periods: systolic acceleration, systolic deceleration, and diastolic, and analyzed to investigate their relationship with the hemodynamic parameters. Results: LBM effectively captured the hemodynamic parameters associated with carotid atherosclerosis with an hourly-based computational cost (2.765 [2.435-3.233] hours). The analysis visualized high TAWSS and low RRT distribution at stenotic areas during the systolic deceleration period and low TAWSS and high RRT distribution at the post-stenotic distal lesion during the diastolic period. These findings were reproducible among the ten patients. Conclusion: LBM-based hemodynamic analysis has the potential to serve as a non-invasive diagnostic tool that can help understand atherosclerosis pathophysiology with low computational cost.